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JPET #87510 Title: MAPK PHOSPHORYLATION in THE JPET Fast Forward. Published on May 18, 2005 as DOI: 10.1124/jpet.105.087510 JPETThis Fast article Forward. has not been Published copyedited andon formatted. May 18, The 2005 final asversion DOI:10.1124/jpet.105.087510 may differ from this version. JPET #87510 Title: MAPK PHOSPHORYLATION IN THE ROSTRAL VENTROLATERAL MEDULLA PLAYS A KEY ROLE IN IMIDAZOLINE (I1) RECEPTOR MEDIATED HYPOTENSION Jian Zhang and Abdel A. Abdel-Rahman Department of Pharmacology and Toxicology Downloaded from Brody School of Medicine East Carolina University jpet.aspetjournals.org Greenville, NC 27834 (ARA and JJ) Tel: (252) 744-3470, FAX: (252) 744-3203 E-mail: [email protected] at ASPET Journals on September 25, 2021 1 Copyright 2005 by the American Society for Pharmacology and Experimental Therapeutics. JPET Fast Forward. Published on May 18, 2005 as DOI: 10.1124/jpet.105.087510 This article has not been copyedited and formatted. The final version may differ from this version. JPET #87510 Running title: RVLM MAPKp42/44 contributes to I1-receptor mediated hypotension Abdel A. Abdel-Rahman Department of Pharmacology and Toxicology, Brody School of Medicine East Carolina University, Greenville, NC 27834 Tel: (252) 744-3470, FAX: (252) 744-3203 E-mail: [email protected] Downloaded from Document statistics: Text pages: 27 jpet.aspetjournals.org Number of figures: 7 Number of tables: 1 Number of references: 26 at ASPET Journals on September 25, 2021 Abstract: 201 words Introduction: 490 words Discussion: 1389 words Abbreviations: α-methylnorepinephrine (α-MNE) Artificial cerebrospinal fluid (ACSF) Mitogen-activated protein kinase (MAPK) Nucleus tractus solitarius (NTS) Phosphatidylcholine-specific phospholipase C (PC-PLC) Rostral ventrolateral medulla (RVLM) 2 JPET Fast Forward. Published on May 18, 2005 as DOI: 10.1124/jpet.105.087510 This article has not been copyedited and formatted. The final version may differ from this version. JPET #87510 Abstract Our previous study showed that rilmenidine, a selective I1-imidazoline receptor agonist, enhanced the phosphorylation of mitogen-activated protein kinase (MAPKp42/44,) via the phosphatidylcholine-specific phospholipase C (PC-PLC) pathway in pheochromocytoma cell line (PC12). In the present study we tested the hypothesis that enhancement of MAPK phosphorylation in the rostral ventrolateral medulla (RVLM) contributes to the hypotensive response elicited by I1 receptor activation in Downloaded from vivo. Systemic rilmenidine (600 µg/kg, i.v.) elicited hypotension and bradycardia along with significant elevation in MAPKp42/44, detected by immunohistochemistry, in RVLM jpet.aspetjournals.org neurons. To obtain conclusive evidence that the latter response was I1-receptor mediated, similar hypotensive responses were elicited by intracisternal (i.c.) rilmenidine µ α α α (25 g/rat) or the highly selective 2-agonist -methylnorepinephrine ( -MNE, 4 at ASPET Journals on September 25, 2021 µg/rat). An increase in RVLM MAPKp42/44 occurred only following rilmenidine. Further, pretreatment with efaroxan (0.15 µg/rat, i.c.), a selective I1-imidazoline receptor antagonist, or with PD 98059 (5 µg/rat, i.c.), a selective ERK1/2 inhibitor, significantly attenuated the hypotensive response and the elevation in RVLM MAPKp42/44 elicited by i.c. rilmenidine. The findings suggest that MAPK phosphorylation in the RVLM contributes to the hypotensive response induced by I1 receptor activation and presents in vivo evidence that distinguishes the neuronal responses triggered by the I1-receptor from those triggered by the α2-adrenergic receptor. 3 JPET Fast Forward. Published on May 18, 2005 as DOI: 10.1124/jpet.105.087510 This article has not been copyedited and formatted. The final version may differ from this version. JPET #87510 Introduction The imidazoline (I1) receptor is considered a novel receptor distinct from the α2- adrenergic receptor (α2-AR) based on the findings: (i) the mixed I1/α2 agonist clonidine and the selective I1 agonists rilmenidine and moxonidine elicit greater hypotensive response when microinjected into the RVLM as compared with the nucleus tractus solitarius (NTS), (ii) the selective α2 agonist α-methylnorepinephrine (α-MNE) elicits appreciable hypotensive response when microinjected into the NTS (Ernsberger et al., Downloaded from 1995; Ernsberger and Haxhiu, 1997), (iii) imidazolinergic and adrenergic receptor signal transduction pathways seem to differ in rabbits (Chan et al., 2005), and (iv) a newly jpet.aspetjournals.org selective I1 receptor agonist LNP509 reduced the blood pressure even in genetically engineered mice lacking functional α2-AR (Bruban et al., 2002; Bousquet et al., 2003). Evidence has shown that the activation of phosphatidylcholine-sensitive at ASPET Journals on September 25, 2021 phospholipase C (PC-PLC) is triggered by I1- receptor in PC12 cells (Separovic et al., 1997; Zhang et al., 2001). The finding that microinjection of D609, a selective PC-PLC inhibitor, into the RVLM attenuated the hypotension caused by systemic moxonidine (Separovic et al., 1997) supports the existence of I1-receptor coupled PC-PLC pathway in vivo. Furthermore, our previous findings in PC12 cells demonstrated that activation of the I1-receptor, which is coupled to PC-PLC, results in downstream activation of mitogen- activated protein kinase (MAPKp42/44) (Zhang et al., 2001). Notably, the PC12 cells, which lack α2-AR (Ernsberger et al., 1995; Separovic et al., 1996), exhibit plasma membrane imidazoline I1 binding sites (Ernsberger et al., 1995). The enhanced phosphorylation of MAPK by the selective I1-receptor agonist rilmenidine and the counteraction of such response by the selective I1-receptor antagonist efaroxan established a clear link between 4 JPET Fast Forward. Published on May 18, 2005 as DOI: 10.1124/jpet.105.087510 This article has not been copyedited and formatted. The final version may differ from this version. JPET #87510 the I1-receptor and the MAPK signal pathway in vitro (Zhang et al., 2001). Whether enhanced phosphorylation of MAPK in vivo is essential for the mediation of the pharmacological action of selective I1 agonists has not been investigated. The objective of the present study was to test the hypothesis that an enhanced neuronal expression of phosphorylated MAPK in the RVLM is functionally linked to the hypotension elicited by I1-receptor activation. To this end, we measured brainstem neuronal MAPKp42/44 (immunohistochemistry) and blood pressure following I1-receptor activation. Downloaded from We focused on the RVLM, the major site of action for the selective I1-receptor agonists such as rilmenidine and moxonidine (Gomez et al., 1991; Haxhiu et al., 1994). However, jpet.aspetjournals.org since rilmenidine exhibits α2-AR agonist activity (Szabo et al., 1993; Regunathan et al., 1995; Zhu et al., 1999) and the RVLM contains both I1- and α2-ARs (Reis, 1996), we investigated the effects of the pure α2-AR agonist α-MNE on MAPK phosphorylation in the at ASPET Journals on September 25, 2021 RVLM. As a control, we investigated whether rilmenidine enhanced the phosphorylation of MAPK in the NTS, which is devoid of functional I1-receptor (Gomez et al., 1991). To confirm the involvement of the I1-receptor and the ERK-MAPK pathway in the observed responses, we investigated the effects of the selective I1-receptor antagonist efaroxan and the ERK1/2 inhibitor PD98059 on the hypotensive response and the enhanced RVLM MAPKp42/44 elicited by rilmenidine. 5 JPET Fast Forward. Published on May 18, 2005 as DOI: 10.1124/jpet.105.087510 This article has not been copyedited and formatted. The final version may differ from this version. JPET #87510 Methods A total 56 Sprague-Dawley (SD) male rats, weighing 320-360 g (Harlan, Indianapolis, IN, USA) were used. All rats were housed in a room with controlled environment at a constant temperature of 23 ± 1°C, humidity of 50 ± 10 % and a 12:12 hours light dark cycle. Food and water were available ad libitum. Surgical procedures and postoperative care were performed in accordance with the Institutional Animal Care and Downloaded from Use Guidelines. Intracisternal cannulation. Four to six days before starting the experiment, we implanted a stainless steel guide cannula into the cisterna magna under pentobarbital jpet.aspetjournals.org anesthesia (50mg/kg, i.p.) as in our previous studies (El-Mas et al., 1994a; El-Mas and Abdel-Rahman, 1998). Briefly, the steel cannula (23 G; Small Parts, FL, USA) was at ASPET Journals on September 25, 2021 passed between the occipital bone and the cerebellum so that its tip protruded into the cisterna magna. The cannula was secured by dental acrylic cement (Duralon: Thomas Dental Supply, Raleigh, NC, USA) as described in our previous studies. The guide cannula was considered patent when spontaneous outflow of cerebrospinal fluid was observed and by gross postmortem histological verification after perfusion with fixation solution. Each rat received a subcutaneous injection of the analgesic buprenorphine hydrochloride (Buprenex; 0.3 µg/rat) and an intramuscular injection of 60.000 U of penicillin G benzathine and penicillin G procaine in aqueous suspension (Durapen). After intracisternal cannulation, the rats were housed individually. Intravascular cannulation. For measurement of blood pressure (BP) and the heart rate (HR), the method described in our previous studies (El-Mas et al., 1994b; El-Mas and Abdel-Rahman, 1998) was adopted. In brief, the rats were anesthetized with pentobarbital 6 JPET Fast Forward. Published on May 18, 2005 as DOI: 10.1124/jpet.105.087510 This article has not been copyedited and formatted. The final version may differ from this version. JPET #87510 sodium (50 mg/kg, i.p.). Catheters (polyethylene 50) were placed in the abdominal aorta and vena cava via the femoral artery and vein for measurement of BP and i.v. administration of drugs, respectively. The catheters were inserted ~ 5 cm into the femoral vessels and secured in place with sutures. The catheters were flushed with heparin (200U/ml). The arterial catheter was connected to a Gould-Statham pressure transducer (Oxnard, CA, USA), and BP was displayed on Grass polygraph (model 7D; Grass Instrument Co., Quincy, MA, USA).
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